April 28, 2006 (Chicago) — Adding a low dose of spironolactone to a standard angiotensin-converting enzyme (ACE) inhibitor reduces albuminuria in patients with type 2 diabetes, according to preliminary findings of a pilot study. The effect was seen in patients with both microalbuminuria and macroalbuminuria, and the addition caused no adverse effects, including no significant hyperkalemia.
"The purpose of this study was to look at patients with type 2 diabetes and albuminuria, which is certainly one of the most prevalent problems we encounter in type 2 diabetes," lead author Michael Benjamin Davidson, DO, from the Cleveland Clinic Foundation in Ohio, told Medscape. Dr. Davidson presented preliminary data on 18 patients here at the 15th annual meeting of the American Association of Clinical Endocrinologists.
"Patients with albuminuria and type 2 diabetes are at increased risk of developing end-stage renal disease (ESRD), and ESRD from diabetes is the most frequent cause of dialysis in this country. We know those patients are also at great risk of developing coronary disease and death from all-cause mortality," he said.
"Despite the widespread use of ACE inhibitors and angiotensin-receptor blockers (ARBs), many continue to have proteinuria. In a number of studies it has been shown that despite ACE inhibitors and ARBs, you can measure elevated levels of aldosterone, and one would presume that, based on the mechanism, that you would suppress aldosterone with those agents."
Preliminary data from other studies has demonstrated a benefit to giving spironolactone in addition to ACE inhibition, Dr. Davidson noted. "We attempted to design a trial that looked at just diabetic nephropathy, and within that, both microalbuminuria and macroalbuminurea."
This open-label pilot intervention trial has an enrollment goal of 40 subjects, with 18 studied to date. The trial requires that subjects visit the clinic 4 times during 12 weeks, with laboratory and clinical assessment at each visit. By design, 20 subjects will have macroalbuminuria (random albumin/creatinine ratio [ACR], 300 mg/g), and 20 will have microalbuminuria (ACR, 100-300 mg/g).
Four weeks after consent, the patient starts spironolactone therapy, and 4 weeks later, stops it. Four weeks after stopping, the patient returns for a follow-up visit. At each visit the patient's blood pressure, metabolic panel, 24-hour urine albumin, and 24-hour urine creatinine levels are recorded.
Study inclusion criteria are: type 2 diabetes; use of any ACE inhibitor, at any dose, for more than 30 days; and a urine albumin/creatinine ratio of 100 mg/g. Exclusion criteria are: creatinine levels higher than 2.0 mg/dL; potassium levels higher than 5.3 mmol/L; uncontrolled hypertension, overt heart failure, or active febrile illness; use of any ARB, spironolactone, or other potassium-sparing diuretic; and nondiabetic renal disease.
Paired t tests and Wilcoxon signed rank tests were applied to compare different visits as appropriate.
Baseline patient characteristics to date (n = 18) are: age, 58.5 ± 9.1 years; African-American race, 6 patients (30%); male sex, 15 patients (75%).
The preliminary group of 18 patients includes 11 with macroalbuminuria and 7 with microalbuminuria. The preliminary conclusion is that adding a low dose of spironolactone once daily for 4 weeks results in a significant decrease in 24-hour creatinine and urine albumin excretion (UAE) levels in patients with type 2 diabetes who are already receiving ACE inhibitors.
"We saw a statistically significant drop in proteinuria after initiating spironolactone," Dr. Davidson told Medscape. "If you look at the percentage drop in the overall 18 patients, [there was a] 26% reduction in the albuminuria after the addition of spironolactone. In the micro group it was 34%, in the macro group, 21%. And those were all statistically significant."
Dr. Davidson added, "There was a concomitant drop in systolic blood pressure when we added spironolactone. However, when we looked at the correlation between albumin excretion, decline in albumin excretion, and decline in systolic blood pressure, they did not correlate. The correlation coefficient was 0.08. So it seems that the drop in systolic blood pressure was not driving the drop in albumin excretion, which I think is a very important finding," he told Medscape.
"No patients withdrew from the study because of adverse effects. "There was no significant hyperkalemia, and I think most clinicians when they hear about adding spironolactone to an ACE inhibitor, you think about hyperkalemia as a significant adverse effect, but there was no significant hyperkalemia," Dr. Davidson said.
Asked whether this study should change clinical practice, Dr. Davidson was cautious.
"I think at this point you can't make the recommendation that every patient with proteinuria be put on spironolactone. Certainly you have to look at patient's renal function. With worsening renal function, you have the potential for developing hyperkalemia when you add those agents such as ACE inhibitors and spironolactone. I think what this does is open the door for larger randomized, prospective trials," he said.
Farhad Zangeneh, MD, assistant clinical professor of medicine at George Washington University School of Medicine in Washington, DC, was even more cautious.
" The safety and efficacy of aldosterone inhibitors in the treatment of proteinuric renal disease remain to be defined, " Dr. Zangeneh told Medscape.
"Because aldosterone escape occurs even in patients taking both an ACE inhibitor and an ARB, there is rationale for using all 3 inhibitors. There is experimental data that suggests that aldosterone may also be important in progressive nephropathy. In experimental hypertensive nephrosclerosis, treatment with Aldactone (spironolactone) is effective in preventing scarring and loss of renal function, and infusion of aldosterone with [a] concomitant ACE inhibitor effectively negates the protection provided by [the] an ACE inhibitor," Dr. Zangeneh said.
He observed that spironolactone has been studied extensively for the treatment of congestive heart failure.
"The Randomized Aldactone EvaluationStudy (RALES), which compared the effect of spironolactone to placebo in addition to standard therapy consisting of an ACE inhibitor, [a]loop diuretic, and digoxin, was stopped early because of a 30%reduction in all-cause mortality in the spironolactone group. A relatively low dose of 25 mg was used, and the effect was independent of the antihypertensive effect. Spironolactone was also well tolerated, with a small but significant rise in serum potassium. These data raise the question of whether aldosterone alone or in combination with other agents that inhibit the [renin-angiotensin system] would be effective for the treatment of progressive nephropathy," Dr. Zangeneh pointed out.
"Of concern is the potential for life-threatening hyperkalemia, particularly in patients with advanced renal insufficiency, or a predisposition to hyperkalemia, such as type 2 diabetics with type 4 renal tubular acidosis," Dr. Zangeneh concluded.
AACE 15th Annual Meeting: Abstract 166. Presented April 27, 2006.
Reviewed by Kristin Richardson